Childhood brain tumor traced to normal stem cells gone bad

Medulloblastomas are driven by mutation-altered stem/progenitor cells of the normal brain, study shows

Keith Ligon, co-senior author of the report

An aggressive childhood brain tumor known as medulloblastoma
originates in normal brain "stem" cells that turn malignant when acted
on by a known mutant, cancer-causing oncogene, say researchers from
Dana-Farber Cancer Institute and the University of California, San
Francisco (UCSF).

Reporting in the August 12 issue of Cancer Cell, the scientists say they have uncovered new origins for these tumors from early stem cells as well as more mature cells.

Previously, scientists had assumed the tumors might only come from a
single source: more mature cells which become neurons and do not have
"stem" cell properties. The findings hint at potential new treatment
approaches for medulloblastoma by targeting the origins of the tumors,
and further suggest that not all patients tumors may be born from the
same cells.

"We now have a better idea of where these brain tumors come from and
their relationship to normal stem cells in the brain," said Keith Ligon, MD, PhD, co-senior author of the report and an investigator at the
Center for Molecular Oncologic Pathology at Dana-Farber and the Brigham
and Womens Hospital.

Co-senior author, David Rowitch, MD, PhD, currently a professor of
pediatrics and neurosurgery at UCSF and a Howard Hughes Medical
Institute investigator, commented that mouse experiments shed light on
how normal stem cells — cells with the power to create all types of
cells in the brain — can be transformed into tumors.

The transformation occurs when a cell-signaling pathway known as
Sonic hedgehog (named for a cartoon character) is reactivated by a
chance mutation.

Sonic hedgehog plays an important role during the embryonic
development of the brain, but normally shuts down when its no longer
needed. When turned on again by a mutation, the signals can trigger cell
processes leading to tumors — not just in the brain, but in other
organs as well.

Medulloblastomas, usually diagnosed in children between 2 and 5 years
of age, affect the brains cerebellum region, which is involved in
controlling body movements. They make up about 30 percent of childhood
brain tumors, and account for 250 to 300 new cases per year. With
current treatments, approximately 60 to 70 percent of patients live at
least five years, but often they are left with cognitive disabilities
from surgery, chemotherapy and radiation, urgently suggesting a need for
new, more-selective therapies.

"Medulloblastoma was one of the first tumors that was believed to fit
the hypothesis that tumors are caused by cancer stem cells that
initiate malignancies and sustain them," said Ligon, who is also on
faculty and an assistant professor at Harvard Medical School. "But the
prevailing hypothesis — that medulloblastomas originate from non-stem
cells — just did not make perfect sense with this."

The discoveries emerged from a series of experiments begun in the
Rowitch Laboratory at Dana-Farber. The initial goal was to determine
whether activating the Sonic hedgehog cancer pathway in multiple types
of brain cells, including neural stem cells, could help pinpoint which
cells brain cancers might come from.

Surprisingly, the scientists generated just one tumor type,
medulloblastoma, regardless of whether they activated the pathway in
stem cells for other cell types called neurons and glia. This was a
surprise: it had been thought that medulloblastoma arose purely from
neuronal ("thinking") cells and not "glial" or supporting cells.

An intriguing question for the investigators is why these cells,
known as granule neuron precursors, seem to be uniquely vulnerable to
the tumor-triggering effects of the Sonic hedgehog pathway, while other
brain stem and progenitor cells are not.

Explained Rowitch: "There must be susceptibility factors in the
granule neuron precursor cell that predispose it to forming cancer, so
we now must try to understand what it is about this cell type that makes
it susceptible to forming cancer in response to Sonic hedgehog
signaling. This relationship between stem cells and oncogenes suggests a
new point of potential therapeutic intervention."

The papers lead authors are Ulrich Schller, MD, an independent researcher in Munich, and Vivi M. Heine, PhD, of UCSF.

The research was supported in part by the National Institutes of
Health, the March of Dimes Foundation, the James S. McDonnell Research
Foundation, and the Pediatric Brain Tumor Foundation of the United
States.

Dana-Farber Cancer Institute (www.dana-farber.org)
is a principal teaching affiliate of the Harvard Medical School and is
among the leading cancer research and care centers in the United States.
It is a founding member of the Dana-Farber/Harvard Cancer Center
(DF/HCC), designated a comprehensive cancer center by the National
Cancer Institute.

UCSF is a leading university dedicated to promoting health worldwide
through advanced biomedical research, graduate-level education in the
life sciences and health professions, and excellence in patient care.
For further information, please visit http://www.ucsf.edu.